Advancing in vivo genome editing: B cell engineering via adenoviral delivery systems
Authors: Amaia Cadinanos-Garai, Mohamed Abou-el-Enein
Journal: Molecular Therapy (2023)

In recent years, adoptive cell therapy has made significant strides in treating various diseases. Yet, the full potential of this promising field remains hindered by complex challenges. Intricate procedures for cell manipulation, high manufacturing costs, extended production timelines, and the risk of adverse effects like off-target toxicities constrain its broader application. 1 Abou-el-Enein M. Elsallab M. Feldman S.A. Fesnak A.D. Heslop H.E. Marks P. Till B.G. Bauer G. Savoldo B. Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy. Blood Cancer Discov. 2021; 2: 408-422 Crossref PubMed Scopus (75) Google Scholar ,2 Flugel C.L. Majzner R.G. Krenciute G. Dotti G. Riddell S.R. Wagner D.L. Abou-El-Enein M. Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours. Nat. Rev. Clin. Oncol. 2023; 20: 49-62 Crossref PubMed Scopus (56) Google Scholar To overcome these obstacles, cutting-edge in vivo gene editing approaches are being developed that necessitate high precision in targeted editing and the use of safe, non-toxic delivery systems, 3 Pfeiffer A. Thalheimer F.B. Hartmann S. Frank A.M. Bender R.R. Danisch S. Costa C. Wels W.S. Modlich U. Stripecke R. et al. In vivo generation of human CD 19- CAR T cells results in B-cell depletion and signs of cytokine release syndrome. EMBO Mol. Med. 2018; 10e9158 Crossref Scopus (95) Google Scholar ,4 Agarwal S. Hanauer J.D.S. Frank A.M. Riechert V. Thalheimer F.B. Buchholz C.J. In Vivo Generation of CAR T Cells Selectively in Human CD4+ Lymphocytes. Mol. Ther. 2020; 28: 1783-1794 Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar ,5 Smith T.T. Stephan S.B. Moffett H.F. McKnight L.E. Ji W. Reiman D. Bonagofski E. Wohlfahrt M.E. Pillai S.P.S. Stephan M.T. In situ programming of leukaemia-specific t cells using synthetic DNA nanocarriers. Nat. Nanotechnol. 2017; 12: 813-820 Crossref PubMed Scopus (0) Google Scholar ,6 Rurik J.G. Tombácz I. Yadegari A. Méndez Fernández P.O. Shewale S.V. Li L. Kimura T. Soliman O.Y. Papp T.E. Tam Y.K. et al. CAR T cells produced in vivo to treat cardiac injury. Science. 2022; 375: 91-96https://www.science.org Crossref PubMed Scopus (348) Google Scholar both of which are paramount in ensuring patient safety (Table 1). Table 1Comparison between main ex vivo and in vivo editing features Criteria Ex vivo engineering In vivo engineering Patient convenience may require cell collection from patient, waiting times no need for cell collection, timely availability Preconditioning preconditioning regimen is recommended may bypass the need for preconditioning Precision & control high precision in manufacturing, quality checks high percision in delivery vector design Validation & efficiency clinically validated, high editing efficiency still under validation, varying efficiency Manufacturing & logistics complex and lengthy process, logistical burden simplified process, minimal logistics Cost & infrastructure high cost, complex infrastructure required generally reduced cost and infrastructure needs Cell fitness considerations possibility of reduced cell fitness due to ex vivo culturing possibility of preserved cell fitness due to direct in vivo editing Toxicity risks controlled ex vivo editing, potential risks of toxicity and off-target effects uncontrolled in vivo editing, increased risk of toxicity and off-target effects Immunogenicity potential risks of immunogenic responses, method-dependent higher risk of immunogenicity Open table in a new tab